John Mihic received his Ph.D. in Pharmacology from the University of Toronto in 1992. He did his postdoctoral work in the Department of Pharmacology at the University of Colorado Health Sciences Center, becoming an Instructor in that department in 1995. In 1997 he moved to the Department of Physiology & Pharmacology at the Wake Forest University School of Medicine, where he contributed to the formation of an NIH-funded Alcohol Research Center. In 1999 he won the 12th annual Young Investigators Award from the Research Society on Alcoholism. Dr. Mihic moved his lab to the University of Texas at Austin in May, 2000 where he is currently an associate professor in the Section of Neurobiology as well as a member of the Waggoner Center for Alcohol & Addiction Research and the Institutes for Neuroscience and Cellular & Molecular Biology. He served a four-year term on the ALTX-3 NIH study section.

Research Summary:Research in my laboratory is focused on developing a better understanding of how ligand-gated ion channels function and how allosteric modulators act on these receptors. Specifically, we use molecular, biochemical and electrophysiological techniques to elucidate the processes underlying receptor activation and allosteric modulation. Most of our current research is conducted on the glycine receptor, a member of the cys-loop receptor superfamily, that also includes the GABA-A, nicotinic acetylcholine and 5HT-3 receptors.

Recently we showed that electrostatic interactions between receptor subunits keep the glycine receptor in a closed-channel state in the absence of neurotransmitter. Breakage of these bonds constitutes an initial step in receptor activation, and the particular inter-subunit interaction we studied also contributes to determining the efficacies of agonists at the glycine receptor. Many allosteric modulators affect members of this receptor superfamily including a number of sedative, hypnotic and anaesthetic agents, such as barbiturates, benzodiazepines, alcohols and volatile and steroidal anaesthetics.

Using whole-cell and single-channel electrophysiology, combined with receptor subunit mutagenesis, we are conducting studies to determine the molecular mechanisms underlying ethanol and volatile anesthetics enhancement of glycine receptor function. In previous work we identified amino acid residues in the second and third transmembrane domains of subunits of GABA-A and glycine receptors that control alcohol and volatile anaesthetic enhancement of receptor function.

An emerging area of research interest in the lab is the use of phage display to identify novel modulators of ion channels. We recently isolated a dodecapeptide as the first potent, efficacious and highly specific allosteric modulator of glycine receptor function. Peptides specifically binding to various isoforms of GABA-A receptors have also been discovered.